<i>N</i>⁶-methyladenosine modification-tuned lipid metabolism controls skin immune homeostasis via regulating neutrophil chemotaxis.

Abstract

Disrupted <i>N</i>⁶-methyladenosine (m⁶A) modification modulates various inflammatory disorders. However, the role of m⁶A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m⁶A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of <i>Mettl3</i> in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m⁶A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m⁶A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m⁶A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m⁶A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m⁶A modulators to attenuate inflammatory skin diseases.